This proposal describes a 5-year-long career development program whose goal is to prepare Dr. Joseph Shieh for a role as an independent investigator. This program will promote his career development by building on his background in genetics and pediatrics by providing expertise in developmental biology. The principal guidance will be provided by the mentor, Dr. Deepak Srivastava, director of the Gladstone Institute for Cardiovascular disease at UCSF. He is a recognized leader in cardiac development and has a record of training independent scientists. The project advisory committee members (Dr. Michael McManus, an expert on microRNA biology; Dr. Didier Stainier, an expert in cardiovascular genetics; and Dr. Robert Nussbaum, an expert in mouse models of human disease) will provide further training. The research program will address heart failure and the potential to alter heart failure by controlling the gene expression changes that characterize failure. The hypothesis is that the small non-coding RNAs called microRNAs play a key regulatory role in heart failure, and Dr. Shieh has identified one of the most highly enriched microRNAs in the human heart and determined that it is important in myogenesis. He developed a mouse model that alters the microRNA level in the heart and found that the mice develop cardiomyopathy. The microRNA triggers characteristic gene expression patterns that are seen in heart failure, suggesting this microRNA is controlling these pathways. In this project, the function of mir-499 in the heart will be assessed in three aims: 1) Dr. Shieh will determine the expression patterns of mir-499 and specific myosin genes in the heart to assign the microRNA to a specific gene regulatory pathway. 2) He will determine whether mir-499 levels exacerbate heart failure in animal models of disease. 3) He will determine the pathway by which mir-499 exerts its regulatory role in heart failure. Research training will be complemented by a formal didactic program in developmental biology, genetics, and ethics. The UCSF Pediatrics Department is committed to Dr. Shieh's career development. UCSF and Gladstone provide an outstanding environment for training independent physician scientists, promoting collaborative research and fostering individual scientific development.